Controlling cardiac fibrosis through fibroblast state space modulation

The transdifferentiation of cardiac fibroblasts into myofibroblasts after cardiac injury has traditionally been defined by a unidirectional continuum from quiescent fibroblasts, through activated fibroblasts, and finally to fibrotic-matrix producing myofibroblasts. However, recent lineage tracing an...

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Bibliographic Details
Published in:Cellular signalling 2021-03, Vol.79, p.109888-109888, Article 109888
Main Authors: Reichardt, Isabella M., Robeson, Kalen Z., Regnier, Michael, Davis, Jennifer
Format: Article
Language:English
Subjects:
Animals
Cardiac fibroblast
Cardiac fibrosis
Cell Differentiation
Cellular Reprogramming
Cellular state space
Fibroblast cell state
Fibrosis
Heart Diseases - metabolism
Heart Diseases - pathology
Humans
Matrifibrocyte
Myofibroblast
Myofibroblasts - metabolism
Myofibroblasts - pathology
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Summary:The transdifferentiation of cardiac fibroblasts into myofibroblasts after cardiac injury has traditionally been defined by a unidirectional continuum from quiescent fibroblasts, through activated fibroblasts, and finally to fibrotic-matrix producing myofibroblasts. However, recent lineage tracing and single cell RNA sequencing experiments have demonstrated that fibroblast transdifferentiation is much more complex. Growing evidence suggests that fibroblasts are more heterogenous than previously thought, and many new cell states have recently been identified. This review reexamines conventional fibroblast transdifferentiation paradigms with a dynamic state space lens, which could enable a more complex understanding of how fibroblast state dynamics alters fibrotic remodeling of the heart. This review will define cellular state space, how it relates to fibroblast state transitions, and how the canonical and non-canonical fibrotic signaling pathways modulate fibroblast cell state and cardiac fibrosis. Finally, this review explores the therapeutic potential of fibroblast state space modulation by p38 inhibition, yes-associated protein (YAP) inhibition, and fibroblast reprogramming. •Cardiac fibroblast cell state is more dynamic and complex than previously thought.•Fibroblast state space can be altered by modulating TGFβ-related pathways.•Changes in fibroblast state modify the global fibrotic response to cardiac injury.•Fibroblast cell state may be a viable target for therapeutic intervention.•YAP and p38 inhibitors have targeted therapeutic potential for modulating fibroblast state space.
ISSN:0898-6568
1873-3913
DOI:10.1016/j.cellsig.2020.109888